Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases

Insulin resistance (IR) is a general phenomenon of many physiological states, disease states, and diseases. IR has been described in diabetes mellitus, obesity, infection, sepsis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, chronic mental stress, and others. In arthritis, abnormalities of glucose homeostasis were described in 1920; and in 1950 combined glucose and insulin tests unmistakably demonstrated IR. The phenomenon is now described in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatica, and others. In chronic inflammatory diseases, cytokine-neutralizing strategies normalize insulin sensitivity. This paper delineates that IR is either based on inflammatory factors (activation of the immune/ repair system) or on the brain (mental activation via stress axes). Due to the selfishness of the immune system and the selfishness of the brain, both can induce IR independent of each other. Consequently, the immune system can block the brain (for example, by sickness behavior) and the brain can block the immune system (for example, stress-induced immune system alterations). Based on considerations of evolutionary medicine, it is discussed that obesity per se is not a disease. Obesity-related IR depends on provoking factors from either the immune system or the brain. Chronic inflammation and/or stress axis activation are thus needed for obesity-related IR. Due to redundant pathways in stimulating IR, a simple one factor-neutralizing strategy might help in chronic inflammatory diseases (inflammation is the key), but not in obesity-related IR. The new considerations towards IR are interrelated to the published theories of IR (thrifty genotype, thrifty phenotype, and others).


Table 1. History of insulin resistance from diff erent perspectives of research in the fi elds of diabetology, infection/ infl ammation, pain, mental activation, trauma, and rheumatology
Year Author Phenomena Reference 1916 Joslin Hyperglycemia in infectious diseases, a painful gallstones, b trauma c [1] 1920 Pemberton and Foster Impaired glucose regulation in soldiers with arthritis a [2] 1924 Rabinowitch Enormous doses of insulin needed in infected diabetic patients a [3] 1929 Root IR in the context of diff erent diseases a,b,c [4] 1936 Himsworth and Kerr Insulin-sensitive and insulin-insensitive diabetes [106] 1938 Thomsen Traumatic diabetes c [107] 1938 Warren β-cell defects in older longstanding diabetic patients In [108] 1950 Liefmann IR in rheumatoid arthritis (combined glucose and insulin test) a [16] 1956 Arendt and Pattee IR in obese subjects [109] 1957 Collins IR in schizophrenia d [110] 1960 Yalow and Berson IR in diabetic subjects (high glucose despite high insulin) [24] 1963 Randle and colleagues Fatty acids support IR [25] 1965 van Praag and Leijnse Major depression induces IR d [111] 1965 Butterfi eld and Wichelow Forearm insulin sensitivity test [112] 1970 Shen and colleagues Quadruple insulin sensitivity test [113] 1979 DeFronzo and colleagues Euglycemic insulin clamp technique in combination with radioisotope turnover, [114] limb catheterization, indirect calorimetry, and muscle biopsy 1979 Wolfe Review: sepsis and trauma induce IR a,b,c [115] 1982 Kasuga and colleagues Insulin induces tyrosine phosphorylation of the insulin receptor [116] 1982 Ciraldi and colleagues Reduced insulin-stimulated glucose uptake in type 2 diabetes [117] 1984 Grunberger and colleagues Dissociation between normal insulin binding and defective tyrosine kinase activity of [118] the insulin receptor 1986 Garvey and colleagues Hyperinsulinemia induces insulin receptor desensitization [119] 1987 Svenson and colleagues IR in rheumatoid arthritis a [17] 1988 Krieger and Landsberg Hypertension, hyperinsulinemia, insulin resistance and SNS [120] 1988 DeFronzo Hyperglycemia decreases glucose transport and inhibits beta-cell function (glucotoxicity) [121] 1988 DeFronzo, Reaven Increased free fatty acids play key role in IR, β-cell dysfunction, and hepatic [121,122] gluconeogenesis (lipotoxicity) 1988 Uchita and colleagues, Pain infl uences IR via the HPA axis and SNS b [123,124] Greisen and colleagues 1992 Feingold and Grunfeld Cytokines like TNF play a role in hyperlipidemia and diabetes a [125] 1993 Hotamisligil and colleagues TNF critically infl uences IR a [34] 1994 Moberg and colleagues Mental stress induces acute IR in type 1 diabetic patients d [126] 1996 Keltikangas and colleagues Mental stress is accompanied by IR in nondiabetic people d [127] 1999 Björntrop IR as a consequence of exaggerated HPA axis and SNS activation (CNS stress is the trigger) d [28] 2000 Chrousos Mental stress-induced hypercortisolism induces IR (the pseudo-Cushing state) d [29] 2000 Seematter and colleagues Mental stress acutely increases insulin-stimulated glucose utilization in healthy lean [128] humans but not in obese nondiabetic humans d 2004 Tso and colleagues Patients with systemic lupus erythematosus demonstrate IR independent of [19] autoantibodies to insulin receptor a 2005 Kiortsis and colleagues, Patients with ankylosing spondylitis and rheumatoid arthritis have IR, which is [20,44] Stagakis and colleagues reduced after anti-TNF therapy a 2007 Larsen and colleagues IL-1ra improved beta-cell secretory function in type 2 diabetic patients (no infl uence on IR) e [129] 2008 Fleischman and colleagues, Salsalate improved insulin sensitivity in young obese adults and in type 2 diabetic patients [43,130] Goldfi ne and colleagues 2010 Schultz and colleagues Patients with rheumatoid arthritis show IR, which can be reduced by blocking IL-6 a [45] 2012, DIAGRAM and colleagues, Human gene polymorphisms link both infl ammation and metabolic disease [93,131] 2014 Fall and Ingelsson approximately 40% of investigated stressed subjects [10][11][12][13][14][15]. At this point the question is why these two disease clusters are linked to IR, which will be addressed in the present paper. Since chronic infl ammatory diseases (CIDs) such as arthritis were among the fi rst to be linked to IR [2,16], newer work in rheumatology has recognized IR in many CIDs [17][18][19][20], cytokine-neutralizing strategies decrease IR in CIDs [20][21][22], and CID patients are at increased risk to develop T2D [23], the special view from rheumatology to IR is understandable and necessary. Th e reader will see that IR is not an endocrine disorder per se, but more a disorder of several systems, better tackled from an interdisciplinary standpoint of neuroendocrine immunology.

Features of insulin resistance and pathophysiology
Originally, IR was defi ned as a subnormal biologic response to a certain insulin concentration, whereby the word subnormal already suggests illness. In the late 1950s, Yalow and Berson developed the radio immunoassay to measure circulating insulin in the blood. In this early paper, they described a state of IR in T2D patients: '… [there is a] lack of responsiveness of blood sugar, in the face of apparently adequate amounts of insulin secreted …' [24]. Th e classical characteristics of IR are presented in Table 2. Elements given in this table work together to induce clinically observed hyperglycemia and very low density lipoprotein hyperlipidemia (trigly cerides) despite elevated insulin levels.
IR is measured by diff erent techniques, whereby the gold standard is the hyperinsulinemic euglycemic clamp and the silver standard is the frequently sampled intravenous glucose tolerance test (Table 3). To study IR or insulin sensitivity in CIDs, simple fasting indices are often used such as the homeostasis model assessment insulin resistance and the Quicki (Table 3), which are adequate when applied in larger clinical studies.

Pathophysiology of insulin resistance -a chronology of models
Th e fi rst viable theory on IR was presented by Randle, who suggested that IR in muscle and adipose tissue is based on the glucose-fatty acid cycle [25]. Th e theory suggested that IR is a consequence of an increased presence of circulating fatty acids and ketone bodies that lead to defects in glucose utilization and an everincreasing insensitivity to insulin. Th e biochemical principles of this model are still valid and useful today.
Further clarifi cation throughout the 1960s and 1970s came from endocrine diseases that were accompanied by IR. Th e explanatory power of hormones is particularly obvious in diseases with an overproduction of a distinct glucogenic hormone such as in Cushing's syndrome (cortisol), acromegaly (growth hormone), pheochromocytoma (catechol amines), glucagonoma, thyro tocicosis (thyroxine, triiodothyronine), and insulinoma (IR as a consequence of insulin receptor desensitization) [5]. Since these diseases were accompanied by IR, the respective hormones became the focus of IR research (called the insulin antagonists; not to speak of antibodies to insulin or insulin receptor). However, in the diseases mentioned in Table 1, IR was not accompanied by enormous serum levels of hormones as in these endocrine tumors.
Physiological conditions and disease states with upregulated stress hormones were found to be accompanied by IR, such as in psychological stress, psychiatric disease, starvation, fasting, and others (Table 1). Th e activation of stress axes is very closely related to the abovementioned cluster of mental activation. For example, an overactive stress system has been described in diff erent forms of IR [26,27]. Stress system activation is an explanatory model for IR, still in vogue [28][29][30][31][32][33], but in 1993 the mainstream of research turned to infl ammation-related IR (discussed in the paragraphs following the next paragraph) [34].
In addition, several authors indicated the central role of the brain because it dictates nutrient intake and foraging behavior. Excess energy intake per se would be an important factor for obesity and, thus, a possible cause of subsequently developing IR. Th is has been demonstrated in humans to play a role in congenital severe obesity with congenital leptin defi ciency [35], or a mutation in the melanocortin receptor type 4 [36]. Th ere is a highly delicate system of hypothalamic regulation of satiety versus food intake, which is infl uenced by distinct pathways within the brain and from the periphery [31,37]. Close relationships exist with psychological components comprising mood disturbances, altered reward perception and motivation, or addictive behavior [38]. Th e interested reader is referred to comprehensive reviews of the subject [31,38,39]. Nowadays, infl ammation-mediated IR is another impor tant explanatory platform of IR in adipocytes, myocytes, and hepatocytes [7,34,40,41]. Disruption of insulin signaling at the level of insulin receptor substrate-1 and insulin receptor substrate-2 and further downstream by tumor necrosis factor (TNF) signaling, toll-like receptor signaling, nuclear factor-κB and inhibitor of nuclear factor-κB, and FoxO1 activation are key elements of infl ammation-related IR [6,40,42]. Crucial cytokines in IR are TNF, interleukin (IL)-1β, IL-6, IL-18, and adipokines. Although the concept behind infl ammationrelated IR is convincing, neutralization of TNF or IL-1β had no infl uence on IR in obese patients or T2D patients [40]. Th is might depend on the redundancy of cytokine pathways because, typically, only one cytokine is neutralized while many cytokines act in parallel. Th is might be overcome by a broader inhibition of proinfl ammatory signaling pathways, which has been shown for salsalate therapy that reduced IR in patients with T2D [43]. In patients with CIDs, TNF and IL-6 neutralizing strategies reduced IR [20,44,45]. Until now it is not clear why the neutralizing strategies perfectly improve insulin sensitivity in CIDs but not in patients without CIDs. Th is discrepancy will be discussed in a model of IR that integrates the fi ndings of CID patients (see below).
In addition to the cytokine-centered theory of IR, a relatively new aspect is nutrient-induced infl ammation that leads to endoplasmic reticulum stress, activation of jun-N-terminal kinase, and inhibition of insulin receptor substrate-1 and AKT (v-akt murine thymoma viral oncogene homolog 1) and, thus, IR in the liver and adipose tissue [6]. In this model of metafl ammation (metabolic infl ammation), free fatty acids can activate toll-like receptors, and free fatty acids and glucose undergoing oxidation in mitochondria stimulate free radical production, both of which inhibit insulin signaling [6,46]. Th e theory describes that nutrient overload in our modern society of affl uence gradually increases the involvement of immune system pathways. Th is leads to ongoing infl ammation, mainly in fat tissue as substantiated by leukocyte infi ltration (the macrophage is the big player). In consequence, involvement of these infl ammatory pathways intensifi es the inhibition of metabolic pathways [6]. In addition, in patients with obesity, changes of the gut microbiota were observed, which in itself can be an infl ammatory factor that contributes to IR [47][48][49].
In this short pathophysiology collection of IR, we recog nize again the two clusters linked to IR: infl ammation with an activated immune/repair system; and increased mental activation (mood, food intake, stress and stress axes). However, the appearance of the two clusters is not yet explained by the interplay of the abovementioned pathophysiological elements. Possibly, published theories on IR with an evolutionary perspective might help to explain the two clusters.

Evolutionary medicine -theories of insulin resistance, 1962 to 2014
Th e theories of IR are summarized in Table 4 and are shortly recapitulated here. Th e thrifty genotype hypo thesis of 1962 states that a gene has been positively selected for an exceptionally effi cient intake and utilization of food, which was good for hunter-gatherers in a feast/ famine environment but is not good for modern people in a world of plenty. In the original theory, a single gene was made responsible for rapid postprandial insulin release that supported quick storage of energy-rich substrates (called the quick insulin trigger) [50,51]. While the original theory focused on the quick insulin trigger, an alternative model focused on possible genes involved in IR [52]. Today, we know that obesity and IR are based on a polygenic background with many single nucleotide polymorphisms with small eff ect sizes. Selection on such mutations would probably be very weak because the individual advantages they would confer would be very small. Th e theory has been criticized due to modest support by genetic analyses; it has been even rejected, but it is still in use and has been adapted by researchers in the fi eld of eating disorders [53].
Another theory of starvation-induced IR proposes that IR of the muscle during fasting is a positively selected program to maintain high circulating glucose levels in order to protect muscle from proteolysis during starvation [52,54]. In addition, during starvation, lipolysis is switched on, leading to provision of free fatty acids and then ketone bodies that can be used by the brain. Both mechanisms spare glucose and glucogenic amino acids in the muscle. IR in the context of starvation is of a special form because insulin levels are very low, no infl ammation accompanies starvation, and counterregulatory hormones such as glucagon and cortisol are continuously upregulated. Th is situation does not apply to IR observed in CIDs and obesity because hyperinsulinemia and infl ammation are a hallmark.
Another important theory of IR is the thrifty phenotype hypothesis [55,56]. Th is model is based on the important observations that underweight babies more often develop IR and obesity compared with normal weight children. In this theory, intrauterine malnutrition and other fetal constraints induce insulin defi ciency (lack of the growth-promoting activities of insulin) and a postnatal state of regulatory IR, which leads to rapid postnatal increase of adipose tissue that remains stable throughout life (accompanied by cardiovascular disease in the older person, and so forth) [57]. In many studies all over the world, the epidemio logical fi ndings were very supportive of the model [55]. Th e theory proposes that environmental factors are the dominant cause of obesity, and that epigenetic intrauterine programming plays the critical role [58,59]. Th is theory has been refi ned in the predictive adaptive response model. In this supplement to the original theory, the relative diff erence in nutrition between prenatal and postnatal environment, rather than an absolute level of nutrition, determines the risk of IR [60]. Both thrifty phenotype theories are accepted in IR research because they have been confi rmed in many studies in humans and animals. Th ese days, it is amazing that a nongenetic theory has received so much support and attention.
Based on the thrifty genotype hypothesis, IR and immune activation were recognized as an adaptive positively selected program to combat infections (the fi ght infections theory of IR). Th e activation of the immune system during infectious disease and infl ammation induces IR, which leads to redirection of glucose to the activated immune system [61]. In a modern form, this was integrated into the concept of immune cell activation by pathogen-sensing and nutrient-sensing pathways (with cytokines, toll-like receptors, jun-Nterminal kinase, and so forth) [62]. Here, even nutrients can induce an infl am matory state that can support IR, which is probably a dilemma after exaggerated food intake when nutrients cannot be adequately stored in fat tissue and elsewhere (nutrient overfl ow problem).
Similarly based on the thrifty genotype theory is the breakdown of robustness theory, which states that a robust glucose control system developed during evolution. Th e breakdown of this robust glucose control system induces positive disease-stabilizing feedback loops leading to IR. Th e critical determinant of the breakdown is TNF [63]. Th is theory incorporates many accepted aspects but TNF is not the sole patho physiological factor.
With the discovery of leptin, a negative feedback loop between adipose tissue and food intake was discovered. While in earlier times many argued that energy homeostasis operates primarily to defend against weight loss, the discovery of the leptin negative feedback loop speaks for homeostatic mechanisms that inhibit uncontrolled weight gain. Th e central resistance model states that central hypothalamic pathways are defective (resistant to leptin and others such as insulin). Th is leads to increased food intake and the resulting obesity induces IR [64]. Th is theory has much value because it added the central regulation of food intake to the peripheral pathophysiologic pathways.
Finally, the good calories-bad calories theory explains that our present food is markedly diff erent from paleolithic food. Particularly, high energy-dense carbohydrates are consumed too often, which induces inadequate hyperinsulinemia [65]. Long-term hyperinsulinemia is the platform for obesity and disease sequelae. Others hypothesized that disparities between paleolithic and contemporary food might be important factors underlying the etiology of common western diseases [66]. Typically the type of ingested lipids and the relative amount of carbohydrates/lipids versus proteins is a problem.
In conclusion, the theories already indicate that IR can be an important aspect to support the brain and the activated immune system. As such, IR can be seen as a positively selected program to support the brain or immune system. In the following sections, this concept is further developed by including aspects of energy regulation.

Energetic benefi ts of insulin resistance for non-insulin-dependent tissue
At this point, I recapitulate that IR increases circulating glucose and free fatty acids that are not taken up in adipose tissue, liver, and muscle, and are now freely available to all non-insulin-dependent tissues. Th e two main profi teers of hyperglycemia are the central nervous system and the immune system because either glucose, free fatty acids (not the brain), or ketone bodies are energetic substrates. Both of these organs do not become insulin resistant. In contrast, the immune system profi ts from insulin because it is an important growth factor for leukocytes and, with the help of insulin, major glucose transporters like glucose transporter-3 and glucose transporter-4 are upregulated on all leukocyte sub populations [67]. In answering the question of whether, for example, hepatic glucose production really provides higher levels of circulating energy, the following simple calculations are presented for glucose (similar calculations can be done for free fatty acids).
One important factor of IR is overproduction of hepatic glucose [68]. In normal subjects, hepatic glucose production after an overnight fast is approximately 2.0 mg/kg per minute. Under a situation involving IR, for example in T2D patients, insulin is 2.5-fold increased and the rate of fasting glucose production can increase to 2.5 mg/kg/minute [68]. After an overnight fast during an observation period of 12 hours, the liver of a normal person of 80 kg bodyweight produces 115 g glucose. Using the above given numbers, a person with IR produces 144 g glucose, leading to an increase of 29 g in 12 hours. An increase of 2 × 29 g = 58 g glucose in 24 hours corresponds to 974 kJ in 24 hours, which is a pretty high number in the light of the normal metabolic rate of 10,000 kJ/day of an 80 kg person (sedentary way of life). Indeed, 974 kJ represents approximately 39% of the total energy need of the normally active central nervous system, or it represents 61% of the energy requirements of all resting immune cells (Table 5). IR is thus a perfect Good calories-bad calories hypothesis: wrong nutrients, particularly carbohydrates, lead to obesity and IR; a paleolithic diet 2010, 2012 [65,66] has quite diff erent qualities that prevents obesity and western diseases ER, endoplasmic reticulum; Ikkβ, inhibitor of nuclear factor-κB kinase β; IR, insulin resistance; JNK, jun-N-terminal kinase; PKC, protein kinase C; PTB-1B, protein tyrosine phosphatase 1B; SOCS3, suppressor of cytokine signaling 3; TLR, toll-like receptor; TNF, tumor necrosis factor. a This is a special form of IR without hyperinsulinemia on the basis of a strong response of counterregulatory hormones. It is questionable to call it IR because of missing hyperinsulinemia and missing infl ammation. In addition, activity of the sympathetic nervous system is low while activity of the hypothalamic-pituitary-adrenal axis is high in the typical nadir.
way to support the activity of the central nervous system, the immune system, and/or other insulin-independent tissues (for example, the heart; Table 5).
In conclusion, while IR is most often regarded as a pathological state to be treated, these numbers and the fact that IR is linked to so many diseases and disease states are indicative of a benefi cial role of IR. While the value of IR can be estimated from the abovementioned numbers, the generation of the two disease clusters is not yet clear.

The selfi sh brain and the selfi sh immune system independently demand energy
Th is section demonstrates aspects of hypothetical character, and the reader is advised to critically judge the theoretical model. Th e basal metabolic rate of the entire body is determined when the following conditions are met [69]: awake, lying, after overnight fast, thermoneutral (no heat production due to low/high temperature), and no emotional stress [69]. Under these conditions, a person weighing 80 kg and 1.80 m in height needs approximately 10,000 kJ/day (Table 5).
Th e so-called minimal metabolic rate is lower than the basal metabolic rate because 15% of energy is spared during sleep, so that a 24-hour sleeping person weighing 80 kg and 1.80 m in height needs 8,500 kJ/day. Th is amount of energy is not up for negotiation between the diff erent organs. Th e delta value between this last number and the maximum of daily energy uptake in the gut (20,000 kJ/day; see Table 5) is 11,500 kJ/day. In this example, 11,500 kJ/day is the controllable amount of energy (CAEN) because allocation of the CAEN to diff erent organs is controlled by the interplay of these organs. Th is amount of energy is available for negotiation. Th e question is which organs are dominant in regulating the CAEN. Dominance can be judged when looking at Table 5, which shows the main users of energy, but can also be derived from simple theoretical considerations.
For example, if a paleolithic hunter experiences tissue trauma with infection, the immune/repair system becomes strongly activated. In this life-threatening situation, regulation of CAEN allocation to the immune/ repair system must be independent of other organs and immediate (hierarchically, the highest level of control to survive). In this situation, circulating cytokines and activated sensory nerve fi bers are responsible for the immediate reallocation of the CAEN to the activated immune system that increases energy consumption (Table 5) [70]. Th is reaction is called the energy appeal reaction [70].
Similarly, if the brain is active during hard forest work over 6 hours, for example, then the skeletal muscles, heart, lungs/diaphragm, and liver are also active, but most other organs are at minimal metabolic levels. Th is is particularly true for the gastrointestinal tract and the immune system. In this example of 6-hour forest work, a person weighing 80 kg and 1.80 m in height would need 18,500 kJ for the entire day (calculated using data from [71]). Th e brain controls the additional CAEN of 10,000 kJ when there is need for forest work. Likewise, if a paleolithic hunter needs to escape from a severe dangerous threat, the brain must control the CAEN. In such a life-threatening situation, the control of the CAEN by the brain must be independent of other organs (again, the highest level of control to survive).
With trauma/infection or fi ght/fl ight response, the activity of most organs depends on either the immune/ repair system or the central nervous system, respectively. We recently delineated that allocation of CAEN to the brain and muscles happens mainly during daytime, while allocation of CAEN to the immune/repair systems happens at night [70]. Th is circadian allocation of energyrich substrates is another clear indication of tight energy regulation. From these theoretical considerations, it becomes clear that either the immune/repair system or the central nervous system is a dominant regulator of the CAEN.
Coming back to the Introduction, with this model the two clusters of clinical entities linked to IR become understandable in terms of energy regulation. One recognizes two independent organs -the selfi sh immune system, and the selfi sh brain [37,72] -related to the abovementioned clusters of infl ammation with an Gastrointestinal tract (including gut immune system, 620 without liver, kidney, spleen) d Kidneys 600 Spleen (erythrocytes plus leukocytes; 90% anaerobic) 480 Lungs d (including lung immune system) 400 Skin d (including skin immune system) 100 a 10,000 kJ = 2,388 kcal. b Activated muscle has a much higher metabolic rate: for example, a Tour de France bicyclist needs approximately 30,000 kJ/day, which is 20,000 kJ more than under sedentary conditions. The 20,000 kJ are used predominantly by the muscles and also the heart. At the upper limit of gastrointestinal resorption, the total body daily uptake (absorptive capacity in the gut) is 20,000 kJ/day. c Moderate activation of the immune system increases daily energy needs to approximately 2,100 kJ/day, and strong activation increases the daily need to 3,000 kJ/day. d Energy need is diffi cult to estimate independent of the immune system in some organs.
activated immune/repair system and of increased mental activation.
With the chronic infl ammatory and chronic mental diseases that induce IR (listed in Table 1), the question arises of whether or not brain-supporting and immune system-supporting IR has been positively selected for acute disease or chronic disease. Such a distinction is not included in the available theories of IR, but it might be helpful to understand the role of IR in general.

A diff erence between acute and chronic disease
While an acute response is often adaptive and physiological to correct alterations of homeostasis, a chronic disease process is often accompanied by the wrong program [70,73]. Looking at simple readout parameters, this can be demonstrated for immune/repair system activation and mental activation.
Th e acute activation of the immune/repair system is outstandingly important to fi ght acute infections and trauma. However, longstanding infl ammation in CIDs leads to severe disease sequelae as summarized recently [70,73]. Th e following disease sequelae are directly linked to CIDs: sickness behavior, anorexia, malnutrition, muscle wasting-cachexia, cachectic obesity, IR with hyper insulinemia, dyslipidemia, increase of adipose tissue near infl amed tissue, alterations of steroid hormone axes, elevated sympathetic tone and local sympathetic nerve fi ber loss, decreased parasympathetic tone, hypertension, infl ammation-related anemia, and osteopenia [70,73]. It was suggested that these sequelae of CIDs are a consequence of a high energy demand of the activated immune/repair system accompanied by water retention [70,73]. Acute activation of the immune/ repair system can be very helpful, but chronic activation is a harmful process that worsens the situation in an aff ected patient.
Considering mental activation, we can also separate acute versus chronic. In the acute situation of emergency for a loved one, family members and hospital staff show strong mental activation that can lead to a higher state of activity, a better readiness to take action, but also poor sleep and symptoms of anxiety [74,75]. Similarly, student's examination stress can lead to a higher state of activity but also to poor sleep and acute increase in anxiety scores [76,77]. Acute examination stress increased intake of highly palatable food in an unproportional manner [78]. In these acute situations, mental activation, poor sleep, and increase in food intake are important to overcome the challenging situation.
However, long-term caregivers of, for example, Alzheimer disease patients are more often obese than noncaregivers, demonstrate alterations typical of the metabolic syndrome, show a higher risk to develop major depression, and have a long-term increase in proinfl am matory markers [79][80][81][82][83][84]. Similarly, chronically stressed students in a highly competitive university environment showed an increased risk of obesity [14]. A dose-response relationship was found between chronic work stress and risk of general and central obesity that was largely independent of covariates such as age, sex, and social position [11], supported in other large studies [12,13]. Moreover, chronic job stress was related to an increased risk of the metabolic syndrome and even T2D [85][86][87]. Chronically poor sleep is related to metabolic risk factors, obesity, and infl ammation [88].
Th is small collection demonstrates that activation of the immune/repair and central nervous systems are successful in acute emergency, but dangerous when applied chronically, leading to typical signs of obesity, metabolic derangement with IR, chronic infl ammation, and increased risk for cardio vascular events [89]. Th e question is why there is such a clear distinction between acute and chronic, which determines the full picture of the metabolic syndrome and IR.

Evolutionary medicine -acute physiological response versus chronic disease
Earlier, it was demonstrated that a highly activated immune/repair system cannot be switched on for a long time because this would be very energy consuming [73]. A highly activated immune system is accompanied by sickness behavior and anorexia, which prevents adequate food intake and necessitates life on stored reserves (infl ammation-induced anorexia). Under systemic infl am matory conditions, breaking down all reserves takes 19 to 43 days [73]. A highly activated immune/repair system can need huge amounts of energy, which is exemplifi ed in the case of extensive burn wounds (up to 20,000 kJ/day) [73]. Although this aspect demonstrates the extreme of the spectrum, it indicates that energy consumption is a critical factor during evolution.
I hypothesize that energy consumption and energy protection are the most critical determinants in evolution, to undergo either negative selection or positive selection, respectively. If alterations of homeostasis lead to marked energy consumption, the situation cannot be chronic -it must be acute. Since the total consumption time ranges between 19 and 43 days [73], an acute energy-consuming change of homeostasis must be started and terminated in this time frame. A very good example for this time window is the germinal center reaction of B-lymphocyte expansion and contraction that happens within approximately 21 to 28 days [90]. Most acute disease states are terminated within this time frame, such as infectious diseases, wound healing, and repair, but also strong mental activation in stressful situations must be termi nated because they are energy consuming, exemplifi ed in short-term stress [78]. During evolution, respective homeostatic networks were positively selected for short-lived, acute, energyconsuming responses but not for longstanding polygenic CIDs or chronic mental illness. Th ese chronic situations generated a huge negative selection pressure.
In contrast, if mutations were helpful to protect energy reserves, they were posi tively selected during evolution. Th is is true for memory responses because immediate reaction of an educated system can spare energy reserves. Th is is exemplifi ed by the immune memory that leads to shorter, more eff ective and, fi nally, less energy-consuming reactions towards microbes. Importantly, acquisition of immune memory during the primary contact must fi t into the above specifi ed time frame of 19 to 43 days (and this happens as exemplifi ed by the germinal center reaction in secondary lymphoid organs). In this context, tolerance versus harmless foreign antigens of microbes on body surfaces (see gut, skin, respiratory tract, urogenital tract) or harmless autoantigens is a memory function that spares energy reserves. Sometimes microbes such as Mycobacterium tuberculosis, Mycobacterium leprae, and viruses enable or mimic tolerant immune responses leading to longstanding infection, but fi nally leading to death due to emaciation.
Similarly, neuronal memory can largely decrease time to accomplish successful foraging in the wild [91]. Neuronal memory systems are tuned to ancestral priorities in the context of foraging and other paleolithic tasks [92]. Additionally, tool-making, invention of language and writing, and storage of data on computer hard disks protects time and thus energy.
Another example of positively selected gene variants is observed for food ingestion and fat storage (not IR!), both of which are important in determining the abovementioned consumption time. Indeed, female Australopithecus afarensis had a consumption time of approximately 19 days, while modern female Homo sapiens can rely on 43 days [73]. Particularly, fat storage has markedly increased over the last 3 to 4 million years of human evolution. Not surprisingly, the latest metaanalysis of genome-wide association studies of obesity and the metabolic syndrome (not IR) found polymorphisms in genes relevant for food intake such as FTO (fat mass and obesity related), MC4R (melanocortin receptor type 4), POMC (proopiomelanocortin, the precursor of melanocortin), and genes relevant for fat storage such as the insulin-stimulating GIPR (gastric inhibitory polypeptide receptor) [93].
Another important indication for positive selection of fat storage networks (not IR) is given by the fact that the number of adipocytes in humans is determined before puberty [57]. After puberty, the number of adipocytes stays constant with an annual exchange rate of 10% [57]. If spontaneous mutations lead to a phenomenon relevant before reproduction time, it will be easily transferred to off spring when it is an advantageous trait. Since the phenomenon still exists in modern children [57], we expect that fat storage was an important factor during evolution. Similarly, humans can deposit large amounts of fat in utero and are consequently one of the fattest species at birth [94]. In addition, newborn humans devote roughly 70% of growth expenditure to fat deposition during early postnatal months, which reduces the risk of energy stress during infections [94]. If the newborns are not able to store large amounts of fat tissue in utero, or if malnutrition is a problem in fetal life (thrifty phenotype model, see above; Table 4), a postnatal program seems to be switched on that supports obesity during childhood and adolescence [55,56]. Again this is an indication that important positively selected gene variants exist that serve storage of energy.
In conclusion, networks are positively selected if they serve acute, highly energy-consuming situations, which are terminated within 3 to 6 weeks. We perceive a chronic disease when it lasts for longer than 6 weeks, as used in classifi cation criteria in RA and juvenile idiopathic arthritis [95]. In addition, gene variants are positively selected if they protect energy stores, which is relevant during the entire life (beyond weeks 3 to 6). Networks that lead to IR serve the acute activation of the selfi sh immune system or the selfi sh brain, but do not belong to networks that protect energy stores (Figure 1). In contrast, IR leads to loss of energy-rich substrates because it is a catabolic process (energy-rich fuels are consumed by non-insulin-dependent organs or are simply excreted) (Figure 1). If the hypothesis of the acute IR program is correct, then chronic IR in chronic infl ammation, in CIDs, and in chronic mental activation or mental disease is a misguided acute program. In contrast to IR, food intake and storage of energy-rich substrates in adipose tissue per se is not a misguided program. In other words, obesity is not dangerous and obesity is not a disease [96]. Yet obesity becomes a problem if additional factors are switched on that usually serve acute energy-consuming situations (mental activation or infl ammation). Per Björntorp once noticed that 'some disease-generating factors, in addition to the basic condition of central obesity, is required for associated diseases to become manifest' [96].

The new model of insulin resistance
With all this information, one can generate a new model of IR that builds upon the existing theories. Th e new model includes four new aspects: it respects much more the immune/repair system, whose energy requirements are enormous (Table 5) [70]; it juxtaposes the selfi sh brain and the selfi sh immune system on a similar hierarchical level in terms of energy demand and requirements (Table 5); it respects that energy requirements convey an evolutionary pressure (highly energyconsuming states are acute (negative selection pressure), energy storage is benefi cial (positive selection pressure)); and it accepts that either immune system activation or mental activation are equally important in inducing IR. On the basis of these elements, a new model of IR is presented in Figure 1. Th is model states that IR is an acute catabolic program to serve the selfi sh immune system or the selfi sh brain, positively selected for infl ammation with an activated immune/repair system and for increased mental activation.
Several testable hypotheses can be generated from the new model, as follows. Obesity is only a problem if acute energy-consuming programs are switched on (either infl ammation or mental activation cause the problem). Immunological tolerance should support the storage function of fat tissue and muscle. Nutrient-induced infl ammation is only a problem if energy-rich fuels are not properly stored (there is an individual storage threshold). Intrauterine constraints (elements of the thrifty phenotype model) should set the thresholds for acute activation programs. While there is a clear link between fat tissue and brain (leptin), there should be similar pathways between the liver/brain and the muscle/ brain that regulate food intake -concerning the muscle/ brain pair, a recent paper found important links through muscle-derived IL-6 [97]. In CIDs, the selfi shness of the immune system should lead to an inhibition of braindependent regulation of energy allocation. Likewise, in mental illness or chronic psychological stress, the selfi shness of the brain should lead to inhibition of the immune system-dependent regulation of energy allocation. In CIDs and mental illness/stress, the two systems must inhibit each other.

The drivers of insulin resistance in chronic infl ammatory and mental diseases
A seminal study demonstrated the interrelation between the dose of subcutaneously injected recombinant human IL-6, serum levels of IL-6, and the increase of energy expenditure in healthy volunteers [98]. Injection of 0.1 μg recombinant human IL-6/kg bodyweight increased serum levels of IL-6 to approximately 10 to 15 pg/ml, 1.0 μg led to 45 pg/ml, 3.0 μg stimulated a serum level of 250 pg/ml, and 10 μg recombinant human IL-6/kg bodyweight was accompanied by an IL-6 serum concentration of more than 1,000 pg/ml. In parallel, the maximal increase of metabolic rate in percent of basal metabolic rate was 4%, 7.5%, 18%, and 25%, respectively [98]. Th is means that a visible infl uence on energy regulation was observed at a serum level of 10 to 15 pg/ml, but the eff ect was small in these healthy volunteers. In contrast, serum levels of 45 pg/ml were related to an increase in metabolic rate of 7.5%, which would amount to approximately 750 kJ/day in a normal-sized healthy subject (basal metabolic rate: 10,000 kJ/day). An increase of serum IL-6 from 1 to 2 pg/ml, as in healthy subjects [99], to 45 pg/ml thus induces a marked energy expenditure program.
Under consideration of the new model in Figure 1, we immediately recognize the problem of continuous infl ammation in CIDs. CIDs such as RA are accompanied by markedly elevated serum levels of IL-6 ranging from 40.0 pg/ml before anti-TNF therapy to 8.0 pg/ml after anti-TNF therapy [100]. Th e levels are thus much higher as compared with healthy subjects (1 to 2 pg/ml [99]). Untreated patients with RA should increase daily energy expenditure by 750 kJ/day (basal metabolic rate: 10,000 kJ/day). Th is value of 750 kJ/day is remarkably similar to the number of 974 kJ/day obtained by hepatic IR as calculated above. Since we expect that several cytokines like TNF, IL-6, interferon gamma, interferon alpha, and others can drive a similar energy reallocation program, elevation of systemic cytokines explains why patients with CIDs do not need any other factor to provoke IR. Th ese CID patients do not need the activation of the brain and thus activation of stress axes to induce IR. Th e brain is silenced in CIDs (sickness behavior). IR can be stimulated by a direct infl uence of cytokines on hepato cytes, adipocytes, and myocytes. We now understand why cytokineneutralizing therapies work perfectly well in RA -because the key IR factor is removed. When cytokine-neutralizing strate gies do not work in obese or T2D people, other parallel factors must play an enormous role.
Th e infl ammatory load is remarkably diff erent in the situation of chronic mental illness or psychological stress where mild peripheral infl ammation probably plays a small supportive role. When one compares serum levels of IL-6 as measured with the identical quantitative highsensitivity enzyme-linked immunosorbent assay technique, healthy subjects range between 1 and 2 pg/ml [99], caregivers show a mean value of 5.5 pg/ml [101], and subjects who report a high level of perceived hopelessness show 3.0 pg/ml [102]. Th ese levels correspond to mild activation of the immune system, but they would not lead to an energy reallocation program [98]. Th us, in mental activation, stress axes must play the major role for the observed IR (cortisol, adrenaline, growth hormone, glucagon). It is expected that neutralization of one cytokine would not change IR in these mentally activated people. Furthermore, when cytokine neutralizing strategies do not work in T2D patients, several factors in parallel are expected to drive IR. It is interesting that salsalate had a positive impact on IR in T2D [43], but this type of drug and other nonsteroidal anti-infl ammatory drugs can also inhibit mental activation in various chronic psychiatric diseases [103][104][105], which is most probably related to reduced activation of stress axes. Upper panel: Acute activation programs were positively selected for short-lived activation of either the brain or the immune system. Hierarchically, the brain and the immune system are on the same level. Activation of the brain mainly stimulates stress axes hormones and activates the sympathetic nervous system (SNS). This is supported by a mild infl ammatory process that is paralleled by mental activation (A). Activation of the immune system induces cytokines, chemokines, and danger signals. In addition, the infl ammatory process uncouples the locally infl amed area from the control of the brain by cytokine-induced hormone/ neurotransmitter production in the periphery independent of superordinate stress pathways. This leads to hepatic cortisol secretion [140], adrenocorticotropic hormone-independent cortisol secretion [141], and production of leukocyte hormones [142] and leukocyte neurotransmitters [143]. The activation of the immune system is accompanied by a mild stimulation of the hypothalamic-pituitary-adrenal axis (HPA) axis (albeit inadequately low in relation to infl ammation) and a somewhat stronger stimulation of the SNS (B). Despite activation of the SNS, anti-infl ammatory neurotransmitters of sympathetic nerve fi bers do not reach the uncoupled infl amed tissue [144]. Infl ammatory and mental activation are often accompanied by anorexia and sickness behavior, which aggravates energy shortage. Lower panel: Chronic energy storage and memory programs were positively selected. The major storage organs are fat tissue (glycerol, free fatty acids) and muscles (proteins). The liver is more a switchboard to interchange and renew energetic substrates. The main storage factor is insulin so that insulin resistance can be seen as a catabolic program induced by catabolic pathways (upper panel). Numbers in red give the typical time of energy provision by the respective organ (amino acids from muscle are spared from day 3 onwards). Storage is mainly supported by a positively selected program of foot intake/foraging behavior and memory. Memory is outstandingly important to spare energy-rich fuels (brain, immune system). Dashed black arrows in the lower panel demonstrate real and hypothetical connections between respective organs. Black numbers give a typical fi gure of stored energy in the respective organs. Dashed black line between upper and lower boxes separates the programs positively selected for acute (catabolic) versus chronic states (storage and memory). CAEN, controllable amount of energy (the energy that is regulated and negotiated between organs); 11βHSD1, 11-beta-hydroxy steroid dehydrogenase type 1 [140].

Conclusions
IR is an unfavorable factor in CIDs because it supports the already activated immune system. IR is a direct consequence of the proinfl ammatory load. Th us, IR should be treated by neutralizing infl ammatory cytokines or by inhibiting the immune system with diseasemodifying anti-rheumatic drugs in a more general way (like salsalate for T2D). Since IR is a very direct consequence of immune system activation, the primary goal is anti-infl ammatory treatment. In CIDs, further treatment of IR beyond good infl ammatory control is expected not to be needed. Since IR is a perfect diagnostic marker of an activated energy reallocation program (infl ammation and mental activation), measuring IR might be a suitable biomarker to study the control of systemic infl ammation in CIDs. Since several cytokines induce IR in a redundant manner, IR might be a more integral systemic diagnostic marker than Creactive protein, the erythrocyte sedimentation rate, or single cytokines.
In addition to aspects of IR in CIDs, this review demonstrates an extended theory of IR that classifi es IR as a benefi cial positively selected program to support activation of the immune/repair system and the brain. IR makes sense in acute alterations of homeostasis in the context of short-lived diseases but is a misguided program in long-term infl ammatory and mental activation.

Key messages
• IR is a consequence of mental activation (neuro endocrine axes) or infl ammation that is a consequence of selfi shness of the brain or the immune system. • IR has been positively selected during evolution for short-lived energy-consuming activation of the brain or immune system. • Long-term IR supports mental disease and CIDs because energy-rich fuels are provided to these noninsulin-dependent tissues (continuous activation). • IR in CIDs is treated by consequent reduction of the proinfl ammatory load. • Treatment of IR in morbid obesity and T2D is more complex because both infl ammatory and neuro endocrine pathways need to be targeted. Th e pleiotropic anti-infl ammatory and central nervous eff ects of salsalate constitute the fi rst positive drug therapy of IR in T2D.